6Y3U

Crystal structure of PPARgamma in complex with compound (R)-16

Summary for 6Y3U

• Entry DOI: 10.2210/pdb6y3u/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, (2~{R})-2-[[6-[(2,4-dichlorophenyl)sulfonylamino]-1,3-benzothiazol-2-yl]sulfanyl]octanoic acid (3 entities in total)
• Functional Keywords: nuclear receptor, inhibitor, steroid hormone receptor, structural genomics consortium, sgc, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 32201.30

Authors

Chaikuad, A.,Hanke, T.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Merk, D.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2020-02-18, release date: 2020-04-22, Last modification date: 2024-01-24)

Primary citation

Hanke, T.,Cheung, S.Y.,Kilu, W.,Heering, J.,Ni, X.,Planz, V.,Schierle, S.,Faudone, G.,Friedrich, M.,Wanior, M.,Werz, O.,Windbergs, M.,Proschak, E.,Schubert-Zsilavecz, M.,Chaikuad, A.,Knapp, S.,Merk, D.
A Selective Modulator of Peroxisome Proliferator-Activated Receptor gamma with an Unprecedented Binding Mode.
J.Med.Chem., 63:4555-4561, 2020

PubMed Abstract: The nuclear peroxisome proliferator-activated receptor γ has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also associated with marked adverse effects and novel modes of PPARγ modulation are required. Here, we report the discovery and profiling of a new PPARγ modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPARγ ligand-binding site. Its -enantiomer evolved as a eutomer regarding PPARγ activation with a high eudysmic ratio. The new PPARγ modulator revealed outstanding selectivity over the PPARα and PPARδ subtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists.

PubMed: 32267688
DOI: 10.1021/acs.jmedchem.9b01786

Experimental method

X-RAY DIFFRACTION (2.62 Å)